Disteroidyl ethers

ABSTRACT

BIOLOGICALLY ACTIVE DISTEROIDYL ETHERS WHEREIN TWO STEROID NUCLEI ARE JOINED TOGETHER BY AN OXYGEN BRIDGE BETWEEN THE CARBON ATOMS IN THE 3-POSITION OF BOTH NUCLEI, HAVING THE FOLLOWING PARTIAL STRUCTURE, ARE DISCLOSED:   ST-O-ST&#39;&#39;   WHEREIN THE WAVY LINE INDICATES THAT THE OXYGEN ATOM LINKED IN POSITION 3 TO THE A RING MAY ASSUME THE A OR B CONFIGURATION, AND THE BROKEN LINE INDICATES AN OPTIONAL DOUBLE BOND IN POSITION 3 FOR THE STERIOD ST AND A DOUBLE BOND IN POSITION 2&#39;&#39; OR 3&#39;&#39; FOR THE STERIOD ST&#39;&#39;; ST IS A STERIOD RESIDUE BELONGING TO THE CHOLANE, CHOLESTANE, ESTRANE, ANDROSTANE AND PREGNANE SERIES, AND THEIR 18-HOMO AND 19-NOR DERIVATIVES; ST&#39;&#39; IS A STEROID RESIDUE BELONGING TO THE ANDROSTANE AND PREGNANE SERIES AND THEIR 18-HOMO AND 19-NOR DERIVATIVES. THESE NEW DISTEROIDYL ETHERS OF THE INVENTION ARE PREPARED BY SUBMITTING A 3-HYDROXY DERIVATIVE OF A STEROID OF THE CHOLANE, CHOLESTANE, ESTRANE, ANDROSTANE, OR PREGNANE SERIES, AS WELL AS THEIR 18-HOMO AND 19-NOR DERIVATIVES, TO TRANS-ETHERIFICATION WITH AN ACTIVATED DERIVATIVE OF A 3-KETOSTEROID OF THE ANDROSTANE, OR PREGNANE SERIES, AS WELL AS OF THEIR 18-HOMO AND 19NOR DERIVATIVES, UNDER ANHYDROUS CONDITIONS AND IN THE PRESENCE OF AN ACID CATALYST.

U i d S at s Pat n US. Cl. 260397.1 Claims ABSTRACT OF THE DISCLOSURE Biologically active disteroidyl ethers wherein two steroid nuclei are joined together by an oxygen bridge between the carbon atoms in the 3-position of both nuclei, having the following partial structure, are disclosed:

I St wt A d t r wherein the wavy line indicates that the oxygen atom linked in position 3 to the A ringmay assume the a or {3 configuration, and the broken line indicates an optional double bond in position 3 for the steriod St and a double bond in position 2' or 3 for the steroid St; St is a steriod residue belonging to the cholane, cholestane, estrane, androstane and pregnane series, and their l8-homo and 19-nor derivatives; St is a steroid residue belonging to the androstane and'pregnane series and their 18-homo land 19-nor derivatives. These new disteroidyl ethers of the invention are prepared by submitting a 3-hydroxy derivative of a steroid of the cholane, cholestane, estrane, androstane, or pregnane series, as well as their 18-homo and 19-nor derivatives, to trans-etherification with an activated derivative of a 3-ket0steroid of the androstane,

or pregnane series, as well as of their 18-homo and 19- e nor derivatives, under anhydrous conditions and in the "presence of an acid catalyst.

GENERAL DESCRIPTION OF THE INVENTION wherein'the broken line indicates the presence of a possible double bond in position 3 of steroid St and of a double bond in positions 2 (3) or 3 (4) in steriod St.

The positions of the steroid moiety St are marked accordingly (i.e., C C C and so on) to distinguish them from the corresponding positions of the other steroid moiety St.

The steroid nucleus St whose carbon atom in position 3 is linked to the oxygen bridge, may belong to the cholane, cholestane, estrane, androstane or pregnane series, as well as to their l8-homo and l9-n0r derivatives; the steroid nucleus St, similarly linked to the oxygen bridge in 3-position, may belong to the androstane or pregnane series, as well as to their l8-homo and 19-nor derivatives.

The process by which the new disteroidyl-ethers of the invention are prepared, consists of submitting, under suitable conditions, a 3-hydroxy steroid of the cholane, cholestane, estrane, androstane, or pregnane series, as well as of their 18-homo and 19-nor derivatives, to trans-etherification with an activated derivative of a 3- ketosteroid of the androstane or pregnane series, as well as of their 18-homo and l9-nor derivatives.

This reaction is carried out under anhydrous conditions, in the presence of an acid catalyst at temperatures between 50 C. and 200 C. for a period of from about 30 minutes to 4 hours. The term activated derivative of 3-ketosteroid is used herein to indicate the typical and well known enolor acetal-derivatives, such as enol ethers, enol esters, hemiacetals or acetals of the 3-keto function, preferably alkyl enol ethers or dialkyl acetals of said 3- ketosteroid.

Included among the preferred embodiments of the compositions of matter of this invention are disteroidyl ethers of the androstane-androstane series, pregnane-pregnane series and androstane-pregnane series represented by the following structural Formulae Ito IV:

( Ra C 11 RT 1 Rs l HIY In the above Formulae I to IV the wavy line indicates that the oxygen atom linked in 3 position to the ring A may assume an or or [3 configuration;

--B wherein A represents hydrogen, an aliphatic or cycloaliphatic radical containing up to 6 carbon atoms or an acyl radical, hereinafter designated Ac, containing up to 8 carbon atoms; B represents hydrogen or a saturated or unsaturated alkyl radical containing up to 4 carbon atoms;

T represents ketonic oxygen or a group (a or 6) where A is hydrogen or an acyl radical containing up to 8 carbon atoms;

X and X, Y and Y each represent hydrogen, a hydroxy group or an acyloxy radical, hereinafter designated OAc, containing up to 8 carbon atoms; and Y further represents a halogen atom, preferably fluorine or chlorine; X and Y' or X and R may form together an acetal bond wherein R represents an alkyl radical containing up to 6 carbon atoms or an aryl radical, and R represents an alkyl or alkoxy radical containing up to 4 carbon atoms; or

may represent a cycloalkyl containing from 5 to 12 carbon atoms.

The hydrogen atom in position 5, if present, may have the a or )3 configuration.

In the compounds of Formulae I to IV the rings A' and B show, according to the structure of the reacting 3- ketosteroid, one of the following structures:

R r R R H H H The rings A and B in the compounds of Formulae I and III may be saturated or show an unsaturation between the carbon atoms in 1:2; 4:5; 5:6 or 5:10 positions, while in the compounds of Formulae II and IV the optional double bond is contained between the carbon atoms in 5:6 position.

The compounds of the invention may show, besides the above mentioned substituents, a methyl radical in positions 1 and 1, thio-acyl groups in positions 1' and 7', an optionally substituted hydroxy group or a halogen atom in position 16 and a methylene bridge in position 1':2'. The 13 and 13' positions may carry an ethyl radical instead of a methyl radical, and position 17 may be further substituted by a cholane or cholestane chain.

Also some 17-spiro lactones of the above compounds are included within the scope of this invention: among them, the compounds in which the 3-ketosteroid moiety consists of the l7-spiro-lactone of 7-acyl substituted compounds and particularly of the 17-spiro-lactone of 3-keto- 7a-acetylthio-androst-4-ene and of its 19-nor analog are particularly interesting.

An object of this invention consists of the compounds of Formula I wherein the alcoholic moiety of the disteroidylether is formed by bile-acids and their derivatives, their salts with alkali metals, their esters with low molecular weight alcohols and particularly their amides formed by reaction with compounds such as glycine and taurine.

A further object of this invention is represented by disteroidyl compounds in which the 3-ketosteroid moiety is formed by aldosterone, l7-isoaldosterone and their derivatives.

The acyl radical, Ac, which is present in the disteroidyl compounds of the invention derives from organic acids containing up to 8 carbon atoms. Particularly, these acids may be saturated or unsaturated organic carboxylic acids, including the aromatic acids, and may contain a straight or branched aliphatic chain or may be formed by a cyclO- aliphatic, arylaliphatic or aromatic group. They may also be substituted by alkoxy or amino groups, halogen atoms and the like. Typical esters are the acetate, propionate, butyrate, valerate, enanthate, caproate and their isomers, the trimethylacetate, aminoacetate, cyclopentylacetate, 13- chloropropionate, cyclopentylpropionate, benzoate, p. chloroor p.fluoro-benzoate and the like, the hemimalonate, hemisuccinate, hemiglutarate and their salts with organic or inorganic bases. Other particularly interesting derivatives are obtained by esterification with inorganic acids, preferably the sulphuric or phosphoric acid.

The aliphatic or cycloaliphatic radical may be straight or branched, saturated or unsaturated and optionally substituted by functional groups. It is typically represented by radicals such as methyl, ethyl, vinyl, propyl, butyl, amyl, hexyl, ethoxyethyl and their isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, l-methoxyoyclohexyl, l-ethoxycyclohexyl, cyclopropylmethyl, tetrahydropyranyl and the like.

The new disteroidyl ethers of this invention exhibit improved and/or increased hormonal properties as compared with those possessed by the two steroid entities. This means that the resulting properties in the new compounds are not merely asum of the activities of the two individual steroid moieties since the disteroidyl compounds show a degree of activity and a biological behavior which are different from those shown by a simple mixture of the two constituting steroids.

In particular, the disteroidyl ethers of Formula I wherein both the C and C carbon atoms have the structure (B being hydrogen or lower saturated alkyl) are androanabolic agents having a favorable anabolic/androgenic ratio. Therefore, the new compounds may be advantageously used in place of androgenic or anabolic agents used in known pharmaceutical preparations and may be orally or subcutaneously administered to patients, the route and dose varying with the nature and the severity of the symptoms to be treated.

Typical derivatives of this class of compounds include:

3,8- 17'fl-propionoxyestra-3',5'-dien-3 -yloxy) -5aandrosta-n-l7-one;

3 ,B-( 17'fl-propionoxyestra-3 ,5 '-dien- -yloxy) 5ocandrost-l-en- 175-01 acetate;

3 5- 17'18-propionoxyestra-3 ,5'-dien-3'-yloxy) -5aandrostan-IZB-ol.

These compounds show a significant androgenic and myogenic effect and are particularly active when administered by oral route.

'Ihe new disteroidyl ethers of Formula I wherein the C carbon atom has the above structure and the C carbon atom has the structure (B being a lower alkenyl or alkynyl radical, i.e. 17'- vinyl, allyl, allenyl, ethynyl, propynyl and the like) possess andro-a-nabolic and progestational activities and therefore are useful as progestinic agents for the treatment of physiological disorders in female animals and in women in a similar manner as known progestins, e.g. progesterone, ethisterone, norethindrone and the like. As a consequence, they have properties which are usually connected with a progestinic activity, i.e. they have effect on the reproductive physiology and exhibit anti-conceptlonal activity.

Representatives of this class of compounds are:

The progestative effect of the above class of compounds is highly potentiated when a 17 a-alkenyl or alkynyl group is also present in the C position, such as in:

These compounds are potent antifertility agents, active by oral or parenteral administration, and can be advantageously used for controlling reproduction in animals.

The disteroidyl ethers of Formula II in which the hydrogen atoms at the 5 and 5 positions have the fl-configuration and the substituents X, X, Y and Y are all hydrogen, show CNS depressant activity. These compounds are useful as sedative, hypnotic or anaesthetic agents.

The disteroidyl ethers of Formula II in which the hydrogen atoms at the 5 and 5 positions have the tat-configuration and wherein Y and Y represent hydrogen, possess progestational activity and are effective in maintaining pregnancy in experimental animals. The following compounds are particularly active:

The disteroidyl ethers of Formula II in which Y and Y are other than hydrogen have mineralcorticoid, glucocorticoid and anti-inflammatory properties and can be used for the treatment of anti-inflammatory conditions in animals and in humans in the same manner as known corticoids. Thus, they can be administered orally in the form of tablets or capsules, or topically as creams, lotions or in the form of ophthalmic suspensions.

Disteroidyl compounds of Formula III and IV may exhibit andro-anabolic activity or andro-anabolic-progestinic activity or anti-fertility and contraceptive activity or cortico-anabolic activity depending from the nature of the steroid components.

Thus, when Y, Y, and X, X represent hydrogen and hydroxy group respectively and the carbon atom in position 17, C have the structure wherein B is hydrogen or lower saturated alkyl, the compounds of the above two Formulae III and IV possess a clear andro-ana-bolic activity.

When Y and Y are represented by hydrogen and X and X are hydrogen or acyloxy group and the carbon atom in position 17, C and 0' have still the structure above defined, the compounds of Formulae III and IV display a definite progestational activity combined with a desired anabolic action. In such compounds it is interesting to note that the progestinic moiety acts as anti-androgenic agent and so improves the anabolic/androgenic ratio of the resulting disteroidyl molecule.

These compounds may be usefully employed in therapy in all those diseases when deficiency of progesterone is noted and anabolic hormones are also prescribed. They are suitable both for oral and subcutaneous treatment.

The progestational activity of the above class of compounds is highly potentiated in those disteroidyl compounds of Formula 111 or IV wherein Y, Y and X, X have the above definitions but the B substituent to the carbon atom in position C (or 0' is represented by a lower alkenyl or alkynyl radical, such as vinyl, allyl, allenyl, ethynyl, propynyl and the like. These compounds are highly effective progestinic agents and also may show contraceptive activity. They are suitable for oral or parenteral administration. Representatives of this class of compounds are:

When in Formulae III or IV Y and Y are other than hydrogen, the compounds display an improved corticoid activity with reduced side elfects, such as a lower catabolic and adrenolitic effect. These positive modifications are due to the activity of the androanabolic moiety of the disteroidyl molecule. Compounds of this kind are particularly interesting as therapeutic agents and can be usefully employed in all those diseases where a corticoid therapy is required. In particular, they have been found interesting anti-inflammatory agents, suitable for oral administration, such as 3B-(9a-fiuoro-l1',20-dioxo-17'a-hydroxy- 21'-hernisuccinoxy 1618 methylpregna-1,3,5'-trien-3'- yloxy)-androst--enl7-one.

A further object of this invention is represented by disteroidyl compounds in which the 3-hydroxysteroid moiety is formed by hormones of the estratriene series, such as, estrone, estriol, 17-epiestrio1, estradiol, 17a-ethinyl estradiol and their l7fi-esters, and the 3-ketosteroid moiety belongs to the class of A -3-ketones having progestational or adreno-cortical activity.

These new disteroidyl ethers may be represented by the following structural formula wherein the broken line in 1:2' position indicates the optional presence of a double bond;

R represents hydrogen or methyl;

R represents hydrogen or a halogen atom;

R represents hydrogen, a hydroxy group or a ketoruc oxygen or a chlorine atom when R is also a chlorine atom;

R represents hydrogen, a methyl radical or a halogen atom;

R represents hydrogen, a halogenation; an a-hydroxy group, free or esterified with an aliphatic acid containing up to 4 carbon atoms; or an a or ,8 methyl radical;

X' and Y each represents hydrogen, a hydroxy group or an acyloxy radical containing up to 8 carbon atoms, and Y further represents a halogen atom;

C represents wherein A represents hydrogen, or an acyl radical containing up to 8 carbon atoms; B represents hydrogen or an ethinyl group; Z is hydrogen, a free or esterified on or 5 hydroxy group or a halogen atom.

Of course, the disteroidyl ethers corresponding to the above formula may display estro-progestinic activity (when Y is hydrogen) or may show estro-corticoid activity (when Y is other than hydrogen), depending to the nature and biological activity of the steroid moiety St. Of particular interest are compounds which incorporate a cortical moiety since they have been found to possess high anti-inflammatory activity and can be advantageously used for the treatment of inflammatory conditions in the same manner as known corticoids.

DESCRIPTION OF THE PROCESS According to the present invention, the process for the preparation of the new disteroidyl derivatives of Formula I consists in reacting a 3-hydroxy derivative of a steroid of the estrane, androstane, pregnane, cholane or cholestane series and their l8-homo and l9-nor derivatives under anhydrous conditions in a suitable solvent and in the presence of an acid catalyst with the enol ether or the acetal of a 3-ketosteroid of the androstane or pregnane series and of their 18-homo and 19-nor derivatives. Benzene, toluene, xylol, dioxane, dimethylformamide and isooctane may be used as solvents, As the acid catalyst, p-toluenesulfonic acid, naphthalenesulfonic acid, pyridine p-toluene sulfonate, and pyridine chlorhydrate, are preferably used. The trans-etherification reaction is eifected at a temperature between 50 C. and 200 C., preferably at a temperature higher than C., for a period of from 30 minutes to 4 hours, as fully described in the examples.

The resulting disteroidyl ether is separated from the reaction mixture, purified and, whether necessary, is further submitted to usual chemical reactions in order to obtain the desired final compound.

The present invention includes all those compounds which may be obtained through obvious reactions, such as saponification which may be carried out on any possible acyloxy group present in the disteroidyl compound; acylation or etherification, by which a desired acyloxy or an ether group may be introduced in place of a free hydroxy group and alkylation generally carried out by means of an appropriate alkyl magnesium halide.

The structure of the disteroidyl derivative obtained throuhg the etherification of a 3(1- or BB-hydroxysteroid with an alkyl or alkylsubstituted enol ether or dialkyl acetal of a keto-steroid as above cited strictly depends from the nature of the steroid itself. The following scheme is given:

Structure of the rings A and B in the disteroidyl Parent 3-keto compound Enolether or acetal starting materials compound 3-keto-5a-steroid enol ether 3-ketd5a-steroid acetal (a) A ene 5a. g-li ti -ggs t e r i d m 3-koto-5B-steroid enol ether- 3-keto-5fl-storoid acetal (b) 13 431191513.

A -3-keto-5a-stcroid A -3-keto-5/3-steroid A -3-keto-steroid N-3-keto-5a-steroid enol eth N-3-keto-5B-steroid enol ether NA-kcto-storoid enol ether A -3-kot0-steroid or la-alkoxy A -3-ketosteroid A- -3-keto ster0id or la-alkoxy-N-Ii-keto- (e) A -triene.

steroid enol ether.

The preferred alkyl-or substituted alkyl-enol ethers are those'contaiuing from 1 to 7 carbon atoms, such as methyl, ethyl-, ,B-halogen substituted ethyl-, propyl-, butylenol ethers and their isomers. Furthermore the cycloalkylenol ethers containing or 6 carbon atoms or an alkyl-enol ether are also used. As acetal, the dimethylor diethylacetal is preferably used.

Preparation of the starting materials (a) and (b) The acetals of saturated 3-ketones (504 or 5;?) may be easily prepared by simultaneous action of an alkyl orthoformate and the corresponding alcohol over the 3-ketone according to Serini and Kosters mthod (Ber. 71, 1766, 1938). The enol ethers of saturated 3-keto steroids (50: or 5e) may also be obtained by reacting the 3-keto steroid with methanol in the presence of an acid catalyst, according to the method of M. Janot et al. (Bull. Franc. 2109, 1961) or to the method of J. Slomp et a1. (J.A.C.S. 77, 1216, 1955). 1

By submitting a dialkyl acetal of the saturated 3-ketone to pyrolysis under analogous conditions to those disclosed by H. H. Inhoffen and Coll. (Ann. 568, 52, 1950), the corresponding enol is obtained. It will have the structure: (a) A ene, 50c if the 3-keto steroid belongs to the series 50:, or the structure (b) A ene-55 if the 3-keto belongs to the series 5,8.

The enol ethers of 3-keto-5ot-steroids having a A -ene structure may be obtained, according to the method described in our U.S. Pat. No. 3,118,917, by catalytic hydrogenation of the double bond in 5-position from the corresponding enol ethers of analogous A -3-ketones (that is ethers of 3-oxy-A -diene steroids), followed by spon taneous migration of the remaining double bond from the 3:4 position to the 2:3 position.

The enol ethers of 3-keto Set-steroids having A -ene structure may be obtained, according to the method described in our U.S. Pat. No. 3,264,329, by catalytic hydrogenation of the corresponding enol ethers of A -3-ketosteroids in the presence of a catalytic amount of a basic substance.

(c)and (c') The enol ethers of A -3-keto-5a-steroids having the A -diene structure may be obtained by submitting the triethers of 1u,3,3-trihydroxy-5a-steroids to pyrolysis as described in British Pat. No. 1,203,278 and as disclosed and claimed in the U.S. Pat. application Ser. No. 830,841 filed June 5, 1969, now abandoned.

The pyrolysis reaction is preferably carried out at a temperature of from 60 C. to 155 C., in the presence of a suitable acid catalyst.

The triethers of la,3,3-trioxysteroids starting materials are in their turn prepared by the process disclosed and claimed in the U.S. Pat. No. 3,475,467. They may be obtained by treating the A -3-keto-5a-steroids with an alcohol and an orthoformate under anhydrous conditions at a temperature lower than 60 C. in the presence of an acid catalyst.

According to the process of the present invention, both 1u,3,3-trialkoxysteroids and the corresponding A -3-keto enol ether may be used for the condensation reaction with the 3-hydroxy steroid but the formers, being the precursors of the enol ethers, have the advantage of a more immediate preparation and therefore, may be preferred starting materials for the preparation of the disteroidyl derivatives having a A -diene structure.

(d) The enol ethers of A -3-ketones may be easily prepared by submitting the A -3-ketosteroid to enol etherification with an alkyl orthoformate or an alcohol, according to well known procedures of the art.

When, as reagent material in the method of the present invention, there is used an enol ether of a A -3-ketone containing a higher alkyl radical than methyl or ethyl, the method disclosed in our U.S. Pat. No. 3,019,241 may be applied to the preparation of such reacting materials. This method consists in submitting the methylor ethyl-enol 10 ether to trans (enol)-etherification by treatment with a higher alcohol. a a

(e) The 3-enolethers of 3-keto-A -steroids may be obtained by enol-etherification of the 3-keto A -pregnadiene with ethyl orthoformate and an alcohol in the presence of a strong acid catalyst as described in the U.S. Pat. No. 3,068,253. In place of the 3-enolethers of 3-keto- A -steroids there may be used, for the preparation of the dis-teroi dyl compounds having a A -triene structure, the corresponding alkyl enol ethers of 1a-alkoXy-A -3- ketones (or 1a,3-dialkoxy-A -dienes). These compounds are obtained by submitting the A -3-keto-steroids to the simultaneous action of an alkyl orthoformate and of the corresponding alcohol under anhydrous conditions at a temperature lower than 60 C., in the presence of a suitable acid catalyst.

The method for preparing la,3-dialkoxy-A -diene steroids of the pregnane series is disclosed in our U.S. Pat. No. 3,506,650. This method may be applied to the preparation of corresponding 1a,3-dialkoxy-A -diene steroids of the androstane series and of their l9-nor or 18-homo derivatives.

The following examples are given to illustrate the invention without limiting it.

In order to make easier the description of the preparation of a number of compounds of the invention, the reacting starting steroids of all examples have been listed in two separated Tables A and B and marked by a progressive number following the letter A or B. In Table A are listed the 3-hydroxy steroids and in Table B are listed the 3-keto-steroids or activated derivatives thereof.

TABLE A A2. Esme-1,3,5(10)-triene-3,17B-diol17-propionate.

A0-- SB-hydroxy-5wandr0stan-1Tone.

A1. 3,6-hydroxy-pregn-5-en-20-one.

An-.. 19-nor-17wpregn-5-en-20-yne-SB,17B-di01 17-aeetate. AL--- 3-hydr0xyestra-1,3,5(10)-trien-17-one.

Am-.- 17a-ethynylestra-1,3,5(10)-triene-3,17B-dio117-acetate. An 3a-hydroxy-Sfl-preguau-ZO-one.

A12-.- 3ahydroxy-5a-andr0stan-17-one.

A1 3a-hydroxy-5B-androstan-17-one.

Au.-- Cho1est-5-en-3B-ol.

A15... Methyl tint-hydroxy-l2a-aeetoxySfi-cholamM-oate. Am 5u-androstane-MJm-dinl 17-aeetate.

A11..- Pregn5-ene-3B20B-diol QO-acetate.

Am--- 36-hydroxyandr0st-4-ene-6,l7-dione.

Am.-- Pregn5-ene-3B,20a-di0l 20-aeetate.

A20.-- 3u-hydroxy-5a-pregnan-20-one.

A22.-- Estra-l,3,5(10)-triene-3,17B-diol 17-acetate.

A23.-. 3-hydroxyestra1,3,5(10)-trieue-6,l7-dione.

A25.-. 3H,17a-dihydroxy-G-methylpregn-5-en-20-one 17-acetate. Am... 3B.17a-dihydroxy-G-ehloropregn-5-en-20eue 17-acetate. A21... 35,17a-dihydroxy-19-n0rpregn-5pn-2O one 17-acetate. A23... 3B-hydroxy-l9-norpregn-5-en-20-one.

A20-.. Estra-1,3,5(10)-triene-3,16a ,17B-triol 16,17-diaeetate. A30..- Estra-l,3,5(10)-triene-3,16B,17B-tri0l16,17-diacetate. A31.-- Estra-1,3,5(10)-triene-3,16a,17a-triol16,17-diacetate. A32. Estra-1,3,5(10)-trien-3,16a,17B-triol 16,17-dipropionate. A33... Estra-1,3,5(10)triene-3J7a-dio117-acetate. SB-pregnaneMflOa-diol QO-acetate. 6a-fluoro-5a-androstaue-36,17B-diol 17-acetate.

A30--- 6a-chlor0-5a-androstane-35,l76-diol 17-acetate.

TABLE B B14.-- 3-ethoxy-17wmethylestra-3,5-dien-17B-ol acetate. B15... 3ethoxyestra 3,5-dien-l7-oue.

B10..- 3-methoxy-9a-fluoro-17a,21-dihydr0xy-16/3methylpregna-l,3,5-

triene-11,20-dione 21-aeetate. B11. 3-ethoxyandrosta-3,5-dien17;3-01 acetate.

TABLE B-Continued TABLE BCoutinued B 3,3-dimethwry-17a-hydroxy-5fi-pregnane-11,20-dione acetate. B11". 3-ethoxy-17a-hydroxy-16-methylenepregua-3,5-dien-20one acetate. B 3 5thoxy-16a.17a-(1'-methylbenzylidenedioxy)pregna-3,5-dienno. 13 3-ethoxy-61z,21-dimethyl-17a-pregna-3,5-dlen-20-yn-17fi-ol acetate. B B-cthoxy-l7a,21-dihydroxypregna-3,5-diene-11,20-dione 2l-acetate.

B 3-methoxy-11 3,17a,21-trihydr0xyprcgua-1,3,5-triene-20-one 15 21-acetate.

B 3-methoicy-9a,11 9-dichloro-17a,21-dihydroxypregna-l ,3,5-tr1en- 20one 21 acetate.

B 3-methoxy-9a,1113-dichloro 17a,21-dihydroxy-lM-methylpregna- 1,3,5-trien-20-one ZI-acetate. B 3-methoxy-9a,11B-diehloro-17a,21-dihydroxy-lfiB-methylpregna- 1,3,5-trien-20one 21-acetate. 20

B11. S-methoxy-Qa-fluoro-IIB,17a,21-trihydroxy-16a-methylpregna- 1,3,5-tricn-20-one 21-acetate.

B11-.. 3-methoxy-9a-fluoro-17a,21.dihydroxy-lfia-methylpregna-l,3,5-

triene11,20-dione 17,21-diaeetate.

B 3-methoxy-Ha-fluoro-11 9,17a,21-trihydroxy-16B-methylpregna- 1,3,5-trien-20one 21-acetate.

B111 3-methoxy-Qa-fluoro-11 3,17a,21-trihydroxy-lG/S-methylpregna- 25 1,3,5-trien-20-one 17,21-diaeetate.

B11. 3-methoxy9a-fl uoro-115,17a,21-trihydroxy-lG-methylenepregna- 1,3,5-trien-20-one 21-acetate.

B11. 3-methoxy-9a-fiuoro17,21-dihydroxy-lG-methylenepregna- 1,3,5-triene11,20-dione 17,21-diacetate.

B 3-methoxy-9a-fluoro-16a,17a-isopropylidenedloxy-2l-hydroxypregna-I,3,5-triene-11,20-dione ZI-acetate.

B 3-ethoxy-6a-iluoro-11B,21-dihydroxy16a,17a-isopropylidenediox y 30 pregua-3,5-dicn-20-one ZI-acetate.

B 3-methoxy-fia-fluoro-lfia,17a-isopropylidenedioxy-Zl-hydroxypregna-1,3,5-trienc-11,20-dione 21-acetate.

B11 3-n1eth0xy-6a,9a-difiuoro-l113,170:,2l-trihydroxypregna-l,3,5-

trien-20-one 17,21-diacctate.

B111. 3-methexy-fia,9a-diiluoro-17a,2l-dihydroxyprcgna-1,3,5-triene- 3 5 11,20-dione 21-acetate. B 3-cthoxy-17a-hydroxyt-methylpregna-3,5-dien-20-one acetate. B5 3-ethoxyandrosta-3,5-dien-l7-one. B11 3-meth0xy-6a,0a-difiuoro-17a,2l-dihydroxypregna-l,3,5-triene- 11,20-dione 17,21-diacetate. B11. 3-methoxy-6a,9a-difiuoro-l1B,17a-dihydroxypregna-1,3,5-trien- 3,3-dimethoxy-5B-pregnan-11,20-dione.

B51. 3-ethoxy-21-hydroxypregna-3,5-dien-20one acetate.

B 3-ethexy-17a-pregna-3,5-dien-2l,17B-carbolaetoue.

B51 3-eth(xg-7a-mercapto-Ua-pregna-Ii,5-dieue-21,17 3-earbolact0ne ace a e.

B11. 3-eth0xy-19-nor-17a-pregna-3,5-dicue-21,17fi-carbolactone.

B11. 3-ethoxy-7a-mcrcapto-19-nor-17a-pregna-3,5-dicue-21,17fl-carbolactone acetate.

B11. 3-ethoxy-11B-methyl-19-n0r-17a-pregna-3,5-dien-20-yn 175-01.

B B-methoxy-Sa-fiuoro-21-hydroxy-1fia-methylprcgna-l,3,5-trieno- 11,20-dione ZI-acetate.

B11. 3-methoxy-6afluoro-11,2l-dihydroxyddm-methylpregna-l,3,5-

trlen--one 21-acetate.

B11. 3-ethoxy-115,1701,21-trihydroxypregna-3,5-dien-2O-one 21-acctate.

l Preparation of corresponding 3-keto-A -steroid is carried out as follows: 10 g. of 6a,9a-diilu0ropredniso1one 17-propionate, described in British Pat. 1,202,001 Example 1, are dissolved in 100 m1. pyridinezmethylene chloride (1:1), cooled t0 0 C. then 15 g. p-toluensulionic aciddissolved in 100 m1. pyridinezmethylene chloride (1:1) are added and the mixture is allowed to rest overnight at 05 C. 6a,0a-diiluoro-11fl,17a,21- trihydroxypregna-1,4-diene 17-propionate 21-tosylate melting at 205- 207 0. thus obtained is dissolved in acetone, treated with g. sodium iodide, refluxed or 24 hours; then 32,75 ml. acetic acid are added and further refluxed for one hour. The mixture is diluted with a 10% aqueous sodium acid sulfite, concentrated under vacuum and extracted with methylene chloride. Removal of the solvent followed by recrystallization from methylene chloridezether afiorded 7.4 g. of 6a,0a-difluoro-11B,17adihydroxypregna-l,4-diene-3,20-dione 17-propionate melting at 235237 0.

EXAMPLE 1 3 a-(l 7'B-propionoxyestra-3,5'-dien-3-yloxy)- SIB-androstanl7-one A solution of 5 g. 3a-hydroxy-5fi-androstan-17-one (A and 5 g. 3-ethoxyestra-3,5-dien-1713-01 (B propionate in 3000 ml. anhydrous benzol containing 100 mg. pyridine tosylate was distilled for 90 minutes until the volume of the solution was reduced to 200-300 ml. After addition of some drops of pyridine the solvent was removed under vacuum and the residue, taken up with methanol, crystallized to give 4.72 g. 3a-(17'fl-p1'0pi011- 0Xyestra-3',5'-dien-3-yloXy)-5B-androstan-17-one melting at 206-209 C. A crystallization from methylene chloridemethanol gives the analytical sample melting at 210-212 C., [a] -3 (c.=1, dioxane).

33-(17fl-acetoxy-2l-methylene-19-nor-17a-pregna-S,5-dien-3-yloxy)-prcgn-5-en-20a-ol acetate 211333 11 1.

B 3 2oi ie lvir pag i tea 17 h dr 1 3 5 t u 20 40 In accordance with the above procedure the following -me oxya, auoroay oxypregnanenediam, pmpionate dlsteroidyl others are obtained.

Preparation Ex. Name from- 2 3 17a-acetoxy-20-oxo re na-3 5'-dien-3-yloxy)-17a-hydroxypregu-5-en-20one acetate A and B 3 21- (17fi-enanthoxy-lyoraTa-pregna-I,,5-dien-20yn-3-yloXy)-19-nor-17a-pregn-5-en-20-yn-17 3-01 cnanthate- A and B 3B-(17B-acetoxy-19-nor-17a-pregna-3,5-dien-20-yn 3-yloxy)-17a-hydroxypregn-5-en-20-one acetate A and B1. 3B-(17fi-proplonoxyestra-3 ,5'-dien-3-yloxy)-5a-androst-l-en-17B-ol te A5 and B1. 3B-(17 3-propionoxyestra-3,5-dien-3-yl0xy)-5a-androstan-17-one A1 and B1. 3B-(17B-acetoxy-l9-n0r-17a-pregna-3',5-dien-20-yn-3-yloxy)-19-nor-17u-pregn-5-en-20-yn-17fi-ol acetate A1 and B1. 8 8-(17-propionoxyestra-B,5'-dien-3-yloxy)-17whydroxypregn-5-en-20-one ace e A1 and B 311-(11,20'-dioX0-17a-hydroxy-Z1-acetoxypregna-1,3,6-t1ien-3-yloxy)-5a-androstan-17B-ol acetate A11 and B1. 311-(17fl-propionoxyestra-3,5-dien-3-yloxy)-5a-androstan-17-one A11 and B1. 3a-(l7fl-aeetoxy-19-nor-17'a-pregna-3,5-dien-20-yn-3'-yloxy)-5a-androstan-17-oue A11 andz. 801-(17 B-acetoxy-19-nor-17a-pregna-3,5-dicn-20'-yn-3-yloxy)-5B-androstan-17-one A11 and B1. 819-(20-oxo-19'-norprcgna-3',5'-dien-3-yloxy)pregn-5-en-20one A and B -(17B-enanthoxy-19-nor-17a-pregna3,5-dien-20-yn-3-yloxy)-pregn-5-en-20-one A and B 35-(6-chloro-17a-acctoxy-20'-oxopregna-3,5-dien-3-yloxy)-pregn-5en-20- A1 and B10. 3B-Ll7B-benzoyloxy-19-ner-17a-pregna-3,5-dien-20-yn-3-yloxy)-prcgn-5-en-20 A and B11. 17 Methyl-(1713-acetoxy-19-nor-17a-prcgna-3,5-dien-20-yn-3-yloxy)-l2a-acetoxy-5Bcholan-24-oate A11 and B1. 18 3B-(17'fl-acet0xy-13'-ethyl-17a-ethinylgona-3,5-dien-3-yloxy)-prcgna-5-en-20-nn A1 and B11. 19 3B-(17B-acetoxy-21-methy1ene-19'-nor-17a-pregna-3,5-dien-3-yloxy)-pregn-5-en-20- A1 and B11. 20 3 3-(17a-acetoxy-20-oxo-6-methylpregna-3,5-dien-3'-yloxy)-pregn-5-en-20- A1 and B11. 21 319-(17fl-acetoxy-17a-mcthylestra-3,5-dien-3-yloxy)-pregn-5-en-20fl-ol ac A11 and B14- 22 3B-(9a-iluoro-11',20'-diox0-17a-hydroxy-ilY-acetoxy-lGfi-methylprcgna-l,3,5,-tr1en-3-yloxy)-androst-5-en-17-one A1 and B11. 23 3 3-(17-acetoxyandrosta-3'.5'-dien-3-yloxy)-androst-4-ene-6,17- A11 and B11. 24 3 9-(17-ox0estra-3,5-dien-3-yloxy)-pregn-5-en-20a-ol acetate A11 and B11. 25 26 52... 3B-(6a-fiuoro11,20-di0xo-21-acetoxy-lfia-methylprcgna-l,3,5-trien-3-yloxy)-androst-5-en-17-one A1 and B6 53--- 3 S-(fia-fluoro-llB-hydroxy-ZO'-oxo-21-acetoxy-l6wmethylpregna-l,3 ,5-trien-3-yl0xy)-audr0st-4-ene6,17-di0ne Ala and B01.

3,B-(17'[3-acetoxy-19-nor 17u-pregna-3',5-dien-20- (B were added to 100 cc. dimethylformamide containyn-3'-yloxy)-9-nor-17u pregn--en-20-yn-17fi-ol acetate 10 ing 125 mg. pyridine tosylate. (Ex. 7) is a high antigonadotrophrc agent and shows A slow nitrogen stream was bubbled in the mixture ovarian inhibition and antiuterotrophic activity. It is which was heated to 175 C. for 60 minutes. active by oral route. As progestimc agent, it is twice as After addition of some drops of pyridine, the residue active as the parent steroid on Clauberg test. The comwas dried under vacuum and taken up with methanol pound possess high contraceptive activity and antifertilcrystallizes to give 4 g. 3,8-(l7'B-acetoXy-l9'-nor-17'- ity effect upon oral administration. p g 2 -yn-3-y1oXy) pregn-5-en-20-one 3,6-(17B-propionoxyestra-3,5-dien 3 y10Xy)-5OL- melting at 225228 C. By crystallization from methylandrostan-l7-one (Ex. 6) is more active than 19-nortestoene chloride-methanol the analytical sample melting at sterone propionate as oral myogenic agent. 232234 C.; M 132 (c.=1, dioxane) was ob- 3p-(l7'a-acetoxy-20'-oxo 6 methylpregna-3',5'-dien- 20 tained. 3'-yloxy)-pregn-5-en-20-one (Ex. 20) shows long-lasting In accordance with the above procedure the following oral activity and high endometrial stimulation. disteroidyl ethers are obtained.

Preparation Ex. Name from- 3(3-(17B-propionoxy-5wandrost-T-en-3-yloxy)-and1'0st-5-enx-17-one A1 and B1. 56-. 3B-(l7B-acetoxy-l9-n0r-l7a-prcgna-3,5-dien-20-yn-3-yloxy)-androst-5-en17-one-.- A1 and B2. 57.- 3w(20-oxo-5B-pregn-3-en-3-Xyloy)-5B-pregnan-20-one Au and Ba. 58.. 3B-17B-propionoxyestra-3,fi-dien-3 -yl0xy)-andr0st-5-en-17-onc A; and B5. 59 3B-(l7'B-acetoxy-19-nor-17a-pregna-3,5-dien-20-yn-3-yloxy)-cholest-5-ene An and B2. 60-- 3B-(l7-ox0estra 3 ,5 -dien-3-yloxy)-pregn-5-en-20fl-ol acetate A17 and B15. 61.- 3w(20-oxo-21-acetoxy 5 8-pregn-3'-en-3-yloxy)-5B-pregnan-20-one A and B18. 62.. 3v:-(20-oxo-2l-acetoXy-5'a-pregnau-2"en-3-yloxy)-5a-pregn-20-one A20 and B19. 63- 3a-(l'l'fi-propionoxyandrost-3-en-3-yloxy)-5B-androstan-17-one.. A13 and B23. 64.-- 3w(20-oxo-5a-pregn-2-en-3-yloxy)-5a-pregnan20-one A20 and B26. 65- 3a-(11',20'diOX0-5'BpIGgn-3-BT1-3'-Y1OXY) -5fl-pregnan-20-one A and B 66.. 3w(17B-acet0xy-6a,21-dimethyl-17a-pregna-3,5-dien-20-yn-3"yloxy)-5B-pregnan-20-one A11 and B31. 67- 3B-(20-oxo-21-acetoxypregna3,5-dien-3-yloxy)-2l-hydroxypregn-5-cn-ZO-one acetate A2; and B54. 68-- 3B-(17-oxoandrosta-3,5-dien-3-yloxy)-androsTr5-en-l7-one A1 and B50.

3ot-(l7'flacetoXyl9'-nor 17'a pregna-3,5-dien-20- 3B-(17,8-acetoXy-19'-nor-l7m-pregna 3,5' dien-20'- yn-3-yloxy)-5u-androstan-17-one (Ex. 11), 3ot-(17fiyn-3'-yloxy)-androst-5-en-l7-one (Ex. 56) shows antiacetoxy-19"-nor-17'wpregna 3',5'-dien 20'-yn-3-yluterotrophic activity, more active than norethindrone oxy)-5B-androstan-l7-one (Ex. 12) show antiuterotroacetate. As progestinic agent is twice as active as the phic activity and are more active than norethindrone 45 parent steroid on Clauberg test. Contraceptive activity acetate. They have endometrial activity as measured on and antifertility upon oral administration.

Clauberg test and are twice as active as norethindrone 3,B-(17B-acetoxy-l9-nor 17'00 pregna-3,5'-dien-20'- acetate, yn-3-yloxy)-pregn-5-en-20-one (Ex. 54) is an antigonadotrophic agent and shows ovarian inhibition and anti- 3a-(17'B-acetoxy-l9' nor-l7'ot-pregna 3',5-dien-20'- uterotrophic acivity. Also orally active progestinic agent,

yn-3-yloxy)-5m-androstan-17-one (EX. 11) is also an 50 orally active myoandrogenic agent. twice as actvie as the parent steroid on Clauberg test.

35-(17/3-enanthoxy-19-nor-17a pregna 3',5'-dien- 20'yn-3'-yloxy)-pregn-5-en-20-one (Ex. 14) and shows E MPLE 69 progestinic activity and is a high lipophilic agent: thus it shows long-lasting effect.

3B-(17u-acetoxy-20-oxo-pregna 3,S-dien-3-yloxy)- 17a-hydroxypregn-5-en-20-one acetate (Ex. 2) is an orally active progestinic, more potent than l7a-acetoxyprogesterone.

3 8-(l7' 8-acetoxy-19-nor-17'u pregna-3,5'-dien-20'- yn-3'-yloxy)-17a-hydroxypregn-5-er1-20-one acetate (EX. 4) is a progestinic agent twice more active than norethindrone acetate. Also antigonadotrophic agent with stimulatory activity. I 65 Zi i ig lgfiigy gg g (gi 3 g gg gg' zggi anol of the fractions eluted with benzene-hexane (8:2), yp eg o a 2.24 g. of analytical pure 3-(17B-BC6tOXy-19-I'lO1-17'oc mg androgenic and myogemc act1v1ty. 1,3,5u0) mew 17-one were obtained, melting at 260-265 (3., EXAMPLE 54 70 A solution of 7 g. estrone (A and 7 g. of 3-ethoxyl9-nor-17a-pregna-3,S-dien-ZO-yn-17,6-01 acetate (B in 60 5000 cc. anhydrous benzene containing 200 mg. p.toluenuesulfonic acid, was distilled for 150 minutes until the volume of the solution was reduced to 400-500 cc. After addition of some drops of pyridine, the solvent was removed under vacuum and the residue was chromatographed on neutral alumina. By crystallization from methyn-3-yloxy) -pregn-5-en-20-one (6:1, dioxane) 5 g. 3B-hydroxypregn-S-en-ZO-one (A and 5.5 g. 3- In accordance with the above procedure the following ethoxy-19-nor-l7u-pregna-3,5 dien-20-yn-l7fl-ol acetate disteroidyl ethers are obtained.

' Preparation Ex. Name from- 70... 3-(l7B-acetoxy-19'-n0r-17'a-pregna3,5-rlierr-20-yn-3-yI0xy)-estra-1.3,5(10)trien-17B-olpropionatc A2 and B1.

3-(17'B-acetoxy-19'-nor-17a-pregna-3,5' dien 20'- berg test. The compound possesses a high contraceptive acyn-3-yloxy)-estra-1,3,5(10)-trien-17 6-ol propionate (Ex. tivity and antifertility effect upon oral administration. 70) displays a contraceptive-sterilizing activity much higher than that of norethindrone enanthate, still evident EXAMPLE 89 in mature female mice 6 months after a single injection. 15 F"( 'fl' y y' 'p 3-(17fl-acetoxy-19-nor-17'a-pregna-3',5 dien 20'- Y '-y Y)'P "Y Y "F Y f l '9 To a solution of 11.7 g. 3B-(1713-acetoxy-19'-n0r-17utate (Ex. 71) displays an interesting long lasting oral 1 5 -2 utefotfophic actlvlty as hlgh as that of qumestrol- 20 54) in 730 cc. methylene chloride and 230 cc. methanol, EXA L 79 4 85 cc. of aidSZb rli ilfthanolic potassitiilm hycgoxigesolut1on were a e e m1x ure was en re x n n1- f trogen atmosphere for 6 hours, then the so l ut ion con- 3 'yloxy)'pregn's centrated under vacuum, diluted with water and the pre- To a solution of 1.7 g. sodium borohydride in 7 cc. e 5 cipitate filtered.Acrystallizaiton from methylene chloridewater, externally cooled with an ice and water bath, 6.7 methanol gives 8.79 g. 3fi-(17fi-hydroxy-19'-nor-17'ug. 3B-(17',8-acetoxy-19-nor-17u-pregna 3',5 dien-20'- pregna-3,5-dien-20'-yn-3'-yloxy)-pregn-5-en-20-one anyn-3-yloxy)-pregn-5-en-20-one dissolved in 130 cc. tetraalytically pure, melting at 270-273 C., [a] -142 hydrofurane were added. The mixture was kept under (c.=1,dioxane).

stirring overnight at room temperature and the solution In accordance with the above procedure the following was then concentrated under vacuum, poured into water disteroidyl ethers are obtained.

Preparation from endproduct of- Ex. Name 19'-nor-17u-pregna-3,5-dien-20'-yn 3 yloxy)pregnyn-3'-yl0xy)-androst-5-en-17/3-ol (Ex. 90) shows an anti- S-en-ZOfl-ol melting at 210-215 C. A crystallization from uterotrophic activity higher than that of norethindrone methylene chloride-methanol gives the analytical sample acetate. Its endometrial activity as measured on Clauberg melting at 214-216" C., [a] =-140 (c.=1, ditest is twice as high as that of norethindrone acetate. oxane) The compound displays also a very high antigonadotrophic In accordance with the above procedure the following activity when administered by oral route in parabiotic disteroidyl ethers are obtained. rats.

Preparation from end- Ex. Name product of- SO 3B-(17B-propionoxyestra-3,5-d.ien-3-yl0xy)-5aandr0stan-17B-ol Example 6. 81.- 3B-(17B-acetoxy-19-nor-17apregna-3',5-dien-20-yn-3-yloxy)-androst-5-en-17B-ol. Example 56.

Example 14.

3;9-(17'13-enanthoxy-19'-nor-17'a-pregna 3',5' dien- 20-yn-3-yloxy)-pregn 5 en 205-01 (Ex. 82) shows a good progestinic activity. 3,8-(17fl-hydroxy 19' nor-17'a-pregna-3',5'-dicn-20- 3{3-(17'fl-hydroxy-21-methylene -19 -nor-17'a-pregnayn-3'-yloxy)-pregn-5-en-20-one (Ex. 89) and 3/3-(17'13- 3,5-dicn-3-y1oxy)-pregn 5 en-ZOfl-ol (Ex. 85) dishydroxy-13'fl-ethyl-17u-ethinylgona-3',5-dien-3-yloxy)- plays a significant activity by oral route in maintaining pregna-S-en-ZO-one (Ex. 92) have a significant end0- pregnancy in rats. metrial activity as measured in Clauberg test.

3/3-(1713-acetoxy 19' nor-17a-pregna-3',5'-dien 20 3fl-(17fl-hydroxy 19' nor-17'a-pregna-3',5'-dien-20- yn-3-yloxy)-androst-5-en-17/3-ol (Ex. 81) is a high antiyn-3-y1oxy)-19-nor-17a-pregn-5-en-20-yn-176-01 (Ex. 96)

gonadotrophic agent, shows ovarian inhibition and antiupossess a significant contraceptive activity. Experiments terotrophic activity. Active by oral route. As progestinic were carried out by weekly administration to female agent, it is twice as active as the parent steroid on Claurats caged with males for three weeks.

'17 EXAMPLE 100 a e-11mm 11',20' dioxo '17"a,21'-dihydroxy-16'B- methylpregna-1',3',5'-trien-3-yloxy) androst-5-en-l7- one v A solution of 1.86 g. of 3,8-(9'a-fluoro-11',20'-dioxo- 17'ot-hydroxy 21' acetoxy-I6'B-methylpregna-1',3',5'- trien- '-yloxy)-androst-5-en-17-one (Ex. 22) in 90 ml. of tetrahydrofuran and 90 ml. of'methanol kept under nitrogen, was treated with 1.86 ml. of 1 M methanol solution of sodium methoxide. After stirring at room temperature for minutes, the solvent was evaporated under reduced pressure and the residue taken up with water and filtered. A crystallization from methylene chloridemethanol gave 1.24 g. of crystal of 3B-(9'a-fluoro-11,20- dioxol7a,2l'-dihydroxy 16',B methylpregna 1,3,5'- trien-3'-yloxy) -androst 5-en-17-one, melting at 260-264 C., [a] -.-77 (c.=1, dioxane).

In accordance with the above procedure the following disteroidyl ethersare obtained.

yloxy)-androst-5-en-17-one (Ex. 100) and 4.2 g. of succinil anhydride in ml. of pyridine was kept overnight at room temperature. The mixture was then poured into 480 ml. of saturated salt solution and extracted with ether. The organic layer was separated, dried on anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue Was crystallized from methyl- .ene chloride-methanol to give 950 mg. of crystals of 3B- (9'a fluoro l1,20' dioxo-17'a-hydroxy-21-hemisuccinoxy 16'5 methylpregna 1',3',5' trien 3 yloxy)- androst-5-en-l7-one, melting at 151-153" C. M -46 (c.=0.5, dioxane).

In accordance with the above procedure using instead of succinic anhydride, the anhydride of the acetic, propionic, butirric, valeric, enanthic, caproic, benzoic, malonic, phthalic and glutaric acid and instead of 36- (9a-fiuoro-11',20' dioxo 17',21'-dihydroxy-16',B-methylpregna-1,3',5'-trien-3'-yloxy)-androst-5-en-l7-0ne any 21-hydr0xy free disteroidyl ether obtained by any preced- 20 ing example the corresponding 21-ester may be pre- EXAMPLE '112 3,8 (9'u fiuono-11',20'-dioxo-17a-hydroxy-21-hemisuccinoxy-16B-methylpregno 1',3,5' trien- '-y1oxy)- androst-5-en-17-one A solution of 1.4 g. of 3B-(9'a-fiuoro-11,20'-dioxo-17', 21'-dihydroxy 167 methylpregna 1',3',5 trien-3- 35 (9'0; fluoro-l1',20-dioxo-17'a-hydroxy-21hemisuccinoxy 16'13 methylpregna 1,3,5' trien 3'- yloxy)-androst-5-en-17-one (Ex. 112) possess a very high oral long-lasting antiinflammatory activity in granuloma pouch test.

Preparation from end- Ex. Name, I p i y Y 7 I product of 1 13...- 3a-(20 oxo-21 hemisuccin0xy-5B-pregn-8-en'3-yloxy)-5fi-pregnan-20-nne Example 101.

114...- 3a- ('20-oxo211hemjsucciu0xy-5 a-pregn-2'-en-3'-yloxy)-5a-pregnan-20-one Example 102- fi-methylpregnal,3,5=trien-3-y1oxy)-21-hyd.roxypregn-5'en-20-one Example 103. p

v Example 109. 121.--- 3'(11',20-diOX0-17'a,21 -dihydroxypregna-ti,5-dien-3-yloxy)-estra 1,3,5(10)-trien-17ao1 l7-ac'etate, 21-hemiphtl1alate- Example 111.

yn-3 '-yloxy)-pregn-5-en-2OB-o1 hemisuccinate A mixture of 2.5 g. 3p-(l7'fl-acetoxy 19"-11OI'-17'oz- 20 EXAMPLE 131 3 B-( 17 'a-acetoxy-20'-oxo-6'-methylenepregna-3',5 '-dien- 3-yloxy)-pregn-5-en-20-ol sulphate sodium salt In a flask provided with a stopper, 9.4 m1. anhydroxy pregna-3',5'-dien-20-yn-3'-yloxy)-pregn-5-en-20B-ol (EX. pyridine and 0.42 ml. acetic anhydride were added to 79) and 7.5 g'. succinic anhydride in 50 ml. pyridine was 0.721 g. anhydrous sulphate pyridine and the mixture kept at 60 C. for 60 hours under nitrogen. The soluwas stirred for 30 minutes. A solution of 1 g. of 3fi-(17'mtion was then poured into ice and water, cautiously acidiacetoxy -20-oxo-16-methylenepregna-3',5'-dien-3-yloxy)- fied with diluted hydrochloric acid and the precipitate pregn-5-en-20'B-ol (Ex. 86) in 10 ml. pyridine was added filtered under vacuum and throroughly washed with water. and the mixture kept under stirring overnight at room A crystallization from methylene chloride-methanol gives temperature, The contents of the flask were evaporated 5% 'l '-P 'g under reduced pressure at 40 C. and the residue was '-Y '-y Y)-P hemisuccinate melting taken up with water, adjusted to a pH 11-12 with a 5% at 1461 9 C- A further Crystallization gives the y 15 aqueous solution of sodium hydrate and extracted with cal Sample melting at 2s= successive portions of n-butanol. Then butanol was re- (c.==1, dioxane). moved by a short heating and the residue, taken up with In accordance with the above procedure using instead h gives 1 3 B.(z17 aceto y-2O'- -16' methy1eneof succinic anhydride, the anhydride of the acetic, proregna-3',5-dien-3'-yl0xy)-pr gnl sulphate, pionic, butirric, valeric, enanthic, caproic, benzoic, 2O di lt, malonic, phthalic and glutaric acid and instead of 3B- In accordance with the above procedure the following (17B acetoxy-19-nor-l7'a-pregna-3,5'-dien-20'-yn-3'- disteroidyl ether is obtained.

Preparation from end- Ex. Name product- 132 3p-[16'a,17a-(1"-methyl-benzylldenedioxy)-20'-oxopregna-3',5'-dlen-3-yloxy]-pregn-5-en-20a-ol sulphate sodium salt Example 99.

yloxy)-pregn-5-en-20B-ol any 17- or 20-hydroxy free disteroidyl ether obtained by any example of the disclosure, the corresponding 17-or ZO-esters may be prepared. In particular the following disteroidyl ethers are obtained.

EXAMPLE 133 Preparation from end- Ex. Name product- 123 3B-(l7B-enanthoxy-l9-nor-17'a-pregna-3 6-dien-20-yn-3-yloxy)-pregn-5-en-20fl-ol hemisuccinate. Example 82.

-5-en-20fl-ol hemisucelnate Example 83.

Example 95. Example 98.

progestinic activity in rabbits. They also show a remark able hypnotic effect in rats by intravenous administration. 36 l7fi-enanthoxy-19-nor-17'rx-pregna-3,5'-dien-20'- yn-3'-yloxy)-pregn-5-en-20,8-ol hemisuccinate (Ex. 123) is an interesting progestinic agent. I

33 (l7'fl-hydroxy-21-methylene-19'-nor-17'a-pregna- 3,5'-dien-3'-yloxy)-pregn-5-en-20a-ol hemisuccinate (Ex. I

127) shows a high progestinic activity in Clauberg test 7 after intravenous treatment. It gives also a significant pregnancy protection in rats after oral treatment.

To a solution of 0.1 ml. of redistilled phosphorus oxychloride in 5 m1. of pyridine is added at 25 C. with stirring a solution of 400 mg. of 3fi-(9'a,ll'fi-dichl0r0- 17a,21'-dihydroxy-20-oxopregna-l',3,5-trien-3-yloxy)- androst-5-en-17-one (Ex. in 5 ml. of anhydrous pyridine. To the dichloride thus formed 20 ml. of water is added at the rate that the reaction temperature does not exceed 10 C. The mixture is then allowed to remain at room temperature for 10 minutes and the pyridine is removed in vacuo without applying external heat. The resulting residue is taken up in water, then sodium bicarbonate solution is carefully added until the mixture reaches pH 7. After extraction with chloroform, the aqueous phase is concentrated under vacuum to dryness. The residue is dissolved in methanol and the 3fi-(9'a,l1'fidichloro-17'a,21'-dihydroxy-2Q+oxopregna-1',3',5' trien- 3'-yloxy)-androst-5-en-17-one 2l'-disodium phosphate precipitated by addition of 1:1 mixture of anhydrous ether and absolute ethanol.

21 22 In accordance with the above procedure the following What is claimed is: disteroidyl ether is'obtained. 1. A disteroidyl ether consisting of two steriod moieties St and St joined together at the C position by an oxygen Preparation I from end- Ex. Name product 134.... 3-(gfiglggcl1,20-dloxo-17a,21dihydroxy-16-methylenepregna-1,3,5-trien-3-yloxy)-estra-1,3,5(10)-trlen-17-one 21-disodium Example 108 EXAMPLE 135 atom, wherein the steroid moiety St is selected from the group consisting of: l B' Y Y' y ,5 (1) an androstane, a l9-norandrostane and a 13-ethylv 3T-Y Y)-17u-methylandrost-5-en-17,8-01 gonan e derivative of the 511- and S B-series, optionally A solution of 5 g. 3B-(17'-oxoandrosta-3',5-dien-3- contanllllg a having at the y y (EX 68) in 100 anhy Q -POSIUOII a substltuent selected from the group condrous tetrahydrofuran was added to 200 ml. of tetrahydroslstmg of hlfdrogen a methyl group, a halogen #9 furan solution of methylma'gnesium bromide prepared and a ketomc oxygen; and having at the C17 Posmon from g. magnesium and 100 metlwlbromida The 20 at least one substituent selected from the group conmixture was refluxed for 6 hours and then decomposed i i a l7'keto i i lm'hydroxy group; with saturated ammonium chloride. Extraction with ether, fl'acy oxy F contammg up to m followed by removal of the solvents under reduced presall ether i sold 17f3-hydroxy group with an aliphatic sure, and recrystallization of the residue from methylene cycloallphatl? rzfdlcal contalmng P to 6 carbon chloride-acetone, afforded 3.4 g. of crystals of 3,8-(17'5- atoms; of a B' Y Y group hydroxy -17'oc -.methylandrosta-3',5-dien-3'-yloxy)-17ugethel' Wlllh a 17'1-10Wef y alkenyl 0r alkynyl methylandrost-5-en-175- 1, group; a combination of an ester of said 17B-hydroxy In accordance with the above procedure using a suitgroup wlth a hydrocarbon carboxylic acid radical able alkylmagnesium halide, the .following disteroidyl c talnlng up to 8 Carbon atoms together with a 17ccethers are obtained. lower alkyl, alkenyl or alkynyl group; and a com- EX. Name Preparation from 136 3B-(17fl-hydroxy-17a-methylestra-3,5-dien-3-yloxy)-pr gn-5-en-20a-01 End-product Ex. 97 and CH3 MgB ,137 3p?(17p-hydroxy-21'-methy1ene-19-nor-17a-preg'na-3',5-dien-3-y1oxy)-pregn-5-en-20wol End-product Ex. 97 and AM 1738 40 bination of an ether of said 17 6-hydroxy group with v V v I an aliphatic or cycloaliphatic radical containing up to 3 e-[17'fi-(l"-ethoxyethoxy)-19-nor-17ut-pregna-3 ,5 6 carbon atoms together with a 17a-lower alkyl,

' '-y '"Y Y]'p alkenyl or alkynyl group;

1 of 2 3 drox re (2) a cholestane derivative selected from the group gfig i i, 5; g i consisting of cholest-S-ene, a lower alkyl ester of 12ain 10 ml. anhydrous tetrahydrofurane and 4 ml. ethylvinyl hydroxy'sfi'cholamc 391d, Q? a lower alkyl ester of ether was treated with ,10 mg. pyridine tosylate and kept Y- B- 01an1c acid, under stirring for 24 hours at room temperature. After (3) an F (lmfmene denvatlve havlng at the addition of some drops of pyridine, the solution was a Substltuent Selected from the group filtered through a thin layer of alumina and the solvent conslsnng of hydrogen l fg a 5- 3" removed under vacuum. The residue taken up with methg group a ester 0 f f l anol crystallized to give 2 g. 3}8-[l7'p-(l"-ethoxyethoxy)- y foxy FP an a a Ogen a and avmg at the C -pos1t1on at least one subst1tuent selected from 'en-ZO-one melting at 140-142 C. A crystallization from the group cfmslstmg of a et0 group; a 17p-hymethylene chloride-methanol gives the analytical sample droxy group a I y n group contalnmg l" to 3 J melting at 14444 1) 1 (2:1, dioxane) carbon atoms; a combination of a l7a-ethynyl group i In accordance with the above procedure the following together Wlth a B- Y Y p; and f comblnadisteroidyl ethers are obtained. tion of a 17a-ethyny1 group together with a 175- E xf Name I Preparation from- 13 3B-[17'B-(1"-ethoxyethoxy)-IB'Bethyl-17'a-ethynylgona-3',5-dien-3-yloxyl-preg'n-fi-eu-Zdone .Q grzildls 3filll7'l3ill"-(fi-chloro-ethoxy):ethozryI-lQB-ethyl-Ua-ethynylgona-3',5'-dien-3'-yloxyl-pregn-fien-Zflone 821E401 In accordance with the procedure of Example 1 the fol- V acyloxy group wherein the acyl group contains up to lowing steroids are further obtained. 8 carbon atoms; and

- 1 Preparation Ex. Name I froma tar-rm. .A 111515 fiII: gg-Ei ]'gg gg r igri a r oyg g ll ri7$3hiii d i'f-fil -yn gg iya2ia-ehloro-5a-androstan-17B-ol acetate A3356 plus B5.

(4) a pregnane of the aand Sfl-series and the corresponding 19-nor and 18-homo derivatives thereof, optionally containing a A bond; having at the C5 position a substituent selected from the group consisting of hydrogen, a methyl group, a halogen atom and a ketonic oxygen; having at the G -position a substituent selected from the group consisting of a hydrogen atom, a hydroxy group, and an acyloxy group containing up to 8 carbon atoms; having at the C -position a substituent selected from the group consisting of a ketonic oxygen, an a-hydroxy group, a B-hydroxy group, an ester of said aand ,B-hydroxy groups with a hydrocarbon mono-carboxylic acid radical containing up to 8 carbon atoms, an ester of said ozand ,8- hydroxy groups with a hydrocarbon di-carboxylic acid radical selected from the group consisting of a hemisuccinyl, hemimalonyl, hemiglutaryl, and a hemiphthalyl radical, and a sulfate or phosphate ester of said aand B-hydroxy groups, and having at the C -position a substituent selected from the group consisting of hydrogen, a hydroxy group, an ester of said hydroxy group with a hydrocarbon mono-carboxylic acid radical containing up to 8 carbon atoms, an ester of said hydroxy group with a hydrocarbon di-carboxylic acid radical selected from the group consisting of a hemisuccinyl, hemimalonyl, hemiglutaryl and a hemiphthalyl radical; and a sulfate or phosphate ester of said 21-hydroxy group;

and wherein the steroid moiety St is selected from the group consisting of:

(1) an androstane, a 19-norandrostane and a 13-ethylgonane derivative of the Sn.- and S S-series, optionally substituted by a methyl group in the C -position, said androstane, 19-norandrostane and 13-ethyl gonane derivative having an unsaturated structure selected from the group consisting of A -ene, A -ene, A diene, A -diene and A -triene; having at the C position a substituent selected from the group consisting of hydrogen, a methyl group, a halogen atom and a ketonic oxygen; having at the C -position a substituent selected from the group consisting of a hydrogen and a halogen atom; having at the C -position a substituent selected from the group consisting of hydrogen, a hydroxy group, a ketonic oxygen, and a chlorine atom; and having at the C position at least one substituent selected from the group consisting of a 17-keto group, a 17,8-hydroxy group, a 17fi-acyloxy group containing up to 8 carbon atoms, an ether of said 17fi-hydroxy group with an aliphatic or cycloaliphatic radical containing up to 6 carbon atoms, a combination of a H S-hydroxy group together with a 17a-lower alkyl, alkenyl or alkynyl group; a combination of an ester of said 17,8-hydroxy group with a hydrocarbon carboxylic acid radical containing up to 8 carbon atoms together with a 17mlower alkyl, alkenyl or alkynyl group; a combination of an ether of said l7 8-hydroxy group with an aliphatic or cycloaliphatic radical containing up to 6 carbon atoms, together with a 17a-lower alkyl, alkenyl or alkynyl group; and a 17-spirolactone group; and

(2') a 20-ketopregnane of the 511- and 5,8-series, and the corresponding 19-nor and 18-homo derivatives thereof, having an unsaturated structure selected from the group consisting of A -ene, A ene, A -diene, A -diene and A -triene; having at the C -position a substituent selected from the group consisting of hydrogen, a methyl group, a halogen atom and a ketonic oxygen; having at the C ,-position a substituent selected from the group consisting of a hydrogen and a halogen atom; having at the (E f-position 24 group containing up to 4 carbon atoms, an ot-methyl group, a fl-methyl group and a methylene group; having at the C -position a substituent selected from the group consisting of hydrogen; a hydroxy group and an acyloxy group containing up to 8 carbon atoms; and having at the C -position a substituent selected from the group consisting of hydrogen, a halogen atom, a hydroxy group, an ester of said hydroxy group with a hydrocarbon mono-carboxylic acid radical containing up to 8 carbon atoms, an ester of said hydroxy group with a hydrocarbon di-carboxylic acid radical selected from the group consisting of a hemisuccinyl, hemimalonyl, hemiglutaryl and a hemiphthalyl radical; and a sulfate or phosphate ester of said 21-hydroxy group; said ZO-ketopregnane derivative being also optionally substituted at the C C positions or at the C C -positions by a lower alkylidenedioxy group. 2. Disteroidyl ethers of formula:

wherein the wavy line indicates that the oxygen atom linked in 3-position to the ring A may assume an a or {i configuration;

R and R each represent hydrogen or methyl;

R represents hydrogen or a halogen atom;

R represents hydrogen, a hydroxy or a ketonic oxygen; or a chlorine atom, where R is also a chlorine atom; R and R each represent hydrogen, a methyl group, a

halogen atom or a ketonic oxygen; C and C' each represent one of the following groups:

wherein A represents hydrogen, an aliphatic or cycloaliphatic radical containing up to 6 carbon atoms or an acyl radical containing up to 8 carbon atoms; B represents hydrogen or a saturated or unsaturated alkyl radical containing up to 4 carbon atoms; with the hydrogen atom in position 5, if present, having an at or ,3 configuration; with the 13 and 13' positions optionally being substituted by an ethyl radical instead of by a methyl radical; the rings A and B optionally being saturated or optionally having an unsaturation between the carbon atoms in 1:2; 4:5; 5:6 or 5:10 positions; the rings A and B' having one of the following structures:

3. Disteroidyl ethers of formula:

CHzY

wherein the wavy line indicates that the oxygen atom linked in 3 position to the ring A may assume an a or ,B configuration; the broken lines indicate the optional presence of a double bond in the 5:6 position;

Rand R each represent hydrogen or methyl;

R represents hydrogen or a halogen atom;

R represents hydrogen, a hydroxy or a ketonic oxygen; or a chlorine. atom, when R is also a chlorine atom;

-R and R each represent hydrogen, a methyl group, a halogen atom oraketonic oxygen;

R represents hydrogen, a'halogen atom, an a-hydroxy I I group free or esterified with an aliphatic acid containing up to 4 carbon atoms; or an 04 or 6 methyl radical;

T represents ketonic oxygen or a group t A (a or B) where A is hydrogen or an acyl radical containing up to 8 carbon atoms;

X and X, Y and Y each represent hydrogen,ra hydroxy group or an acyloxy radical containing up to 8 carbon atoms, and Y further represents a halogen atom; or

X and Y or X and R may form together an acetal bond -wh erein R represents an alkyl radical containing up to ,6carbon atoms or an aryl radical, and R represents an alkyl or alkyloxy radical containing up to 4 carbon atoms;

,or, I

may repre'sent a cycloalkyl containing from 5 to 12 car- 7 bon atoms; withthe hydrogen atom in 5 position, if present, having an a or B configuration; with the 13 and 13,

positions optionally being substituted by an ethyl radical instead of by a methyl radical; the, ringsA' and B having one of the following structures;

4. Disteroidyl ethers of formula:

wherein the wavy line indicates that the oxygen atom linked in 3 position to the ring A may assume an a or ,3 configuration; C represents one of the following groups:

wherein A represents hydrogen, an aliphatic or cycloaliphatic radical containing up to 6 carbon atoms or an acyl radical containing up to 8 carbon atoms; and B represents hydrogen or a saturated or unsaturated alkyl radical containing up to 4 carbon atoms;

R and R each represent hydrogen or methyl;

R represents hydrogen or a halogen atom;

R represents hydrogen, a hydroxy or a ketonic oxygen; or a chlorine atom, when R is also a chlorine atom;

R and R each represent hydrogen, a methyl group, a

halogen atom or a ketonic oxygen;

R represents hydrogen, a halogen atom, an u-hydroxy group free or esterified with an aliphatic acid containing up to 4 carbon atoms; or an a or ,B-methyl radical;

X and Y each represent hydrogen, a hydroxy group or an acyloxy radical containing up to 8 carbon atoms; and Y further represents a halogen atom; or

X and Y or X and R may form together an acetal bond wherein R represents an alkyl radical containing up to 6 carbon atoms or an aryl radical, and R represents an alkyl or alkyloxy radical containing up to 4 carbon atoms;

may represent a cycloalkyl containing from 5 to 12 carbon atoms; with the hydrogen atom in position 5, if present, having an a or e configuration; with the 13 and 13' positions optionally being substituted by an ethyl radical insteadrof by a methyl radical; the rings A and B optionally being saturated or optionally having an unsaturation between the carbon atoms in 1:2; 4:5; 5:6 or 5:10 posi- 27 tions; the rings A and B' having one of the following structures:

R R R s H s (a) (b) (c) R R Q3 m (d) 5. Disteroidyl ethers of formula:

wherein the wavy line indicates that the oxygen atom linked in 3 position to the ring A may assume an a or )3 configuration; the broken line indicates the optional presence of a double bond in the :6 position;

R and R each represent hydrogen or methyl; R represents hydrogen or a halogen atom; R represents hydrogen, a hydroxy or a ketonic oxygen;

or a chlorine atom, when R is also a chlorine atom; R and R each represent hydrogen, a methyl group, a

halogen atom or a ketonic oxygen; C' represents one of the following groups:

wherein A represents hydrogen, an aliphatic or cyclo-aliphatic radical containing up to 6 carbon atoms or an acyl radical containing up to 8 carbon atoms, and B represents hydrogen or a saturated or unsaturated alkyl radical containing up to 4 carbon atoms;

T represents ketonic oxygen or a group where A is hydrogen or an acyl radical containing uu to 8 carbon atoms;

X and Y each represent hydrogen, a hydroxy group or an acyloxy radical containing up to 8 carbon atoms;

with the hydrogen atom in position 5, if present, having an a or [3 configuration; with the 13 and 13' positions optionally being substituted by an ethyl radical instead of by a methyl radical; the rings A and B having one of the following structures:

t E H (a) (b) (0) 6. Disteroidyl derivatives of formula:

wherein the broken line in 1:2 position indicates the 0ptional presence of a double bond;

R presents hydrogen or methyl;

R represents hydrogen or a halogen atom;

R represents hydrogen, a hydroxy group or a ketonic oxygen; or a chlorine atom when R is also a chlorine atom;

R represents hydrogen, a methyl radical or a halogen atom;

R represents hydrogen, a halogen atom, an a-hydroxy group, free or esterified with an aliphatic acid containing up to 4 carbon atoms, or an aor fl-methyl radical;

X' and Y each represents hydrogen, a hydroxy group or an acyloxy radical containing up to 8 carbon atoms, and

Y further represents a halogen atom;

C represents wherein A represents hydrogen or an acyl radical containing up to 8 carbon atoms; B represents hydrogen or an ethinyl group; Z is hydrogen, a free or esterified aor ,3- hydroxy group or a halogen atom.

7. 3-(17B-hydroxyor lower acyloxy-19'-nor-17'a-pregna 3,5 dien 20 yn 3' yloxy) estra 1,3,5(10)- trien-l7fi-ol and the corresponding 17-lower alkanoate.

8. 3 (17'5 hydroxyor lower acyloxy 19'-nor-17ocpregna 3,5' -dien 20 yn 3' yloxy) 17a ethynylestra-l,3,5(10)-trien-l7B-ol the corresponding l7-lower alkanoate.

9. 3fi-(17'a-acetoxy-20-oxopregna-3',5'-dien-3-yloxy)- 17a-hydroxypregn-5-en-20-one acetate.

10. 3B-(17'fl-acetoxy-19'-nor-1Tot-pregna-3',5-dien-20'- yn-3-yloxy)-17a-hydroxypregn-5-en-20-one acetate.

11. 3B (1738 propionoxyestra 3,5 dien 3'-yloxy- 5a-androstan-17-one.

12. 3B (17'5 acetoxy -19' nor -17'a pregna 3',5- dien-20-yl-3'-y1oxy)-androst-5-en-l7-one.

13. 3p (IT 3 acetoxy 19'-nor-17'a-pregna-3,5-dien- 20-yn- -yloxy)-pregn-5-en-20-one. 

